Francis S. Collins, Eric D. Green, Alan E. Guttmacher and Mark S. Guyer- A vision for the future of genomics research: A blueprint for the genomic era

8/3/2019 Francis S. Collins, Eric D. Green, Alan E. Guttmacher and Mark S. Guyer- A vision for the future of genomics researc

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Francis S. Collins, Eric D. Green,Alan E. Guttmacher and Mark S.Guyer on behalf of the US NationalHuman Genome Research Institute*

The completion of a high-quality,comprehensive sequence of thehuman genome, in this fiftiethanniversary year of the discovery of thedouble-helical structure of DNA, is alandmark event. The genomic era isnow a reality.

In contemplating a vision for thefuture of genomics research,it is appropri-ate to consider the remarkable path thathas brought us here. The rollfold(Figure 1) shows a timeline of land-mark accomplishments in geneticsand genomics, beginning with GregorMendels discovery of the laws of heredity1

and their rediscovery in the early days of thetwentieth century.Recognition of DNA as thehereditary material2, determination of itsstructure3, elucidation of the genetic code4,development of recombinant DNA tech-nologies5,6, and establishment of increasinglyautomatable methods for DNA sequen-

cing710

set the stage for the Human GenomeProject (HGP) to begin in 1990 (see alsowww.nature.com/nature/DNA50). Thanksto the vision of the original planners, andthe creativity and determination of a legionof talented scientists who decided to makethis project their overarching focus, all ofthe initial objectives of the HGP have nowbeen achieved at least two years ahead ofexpectation, and a revolution in biologicalresearch has begun.

The projects new research strategies andexperimental technologies have generated asteady stream of ever-larger and more com-

plex genomic data sets that have poured intopublic databases and have transformed thestudy of virtually all life processes. Thegenomic approach of technology develop-ment and large-scale generation of commu-nity resource data sets has introduced animportant new dimension into biological andbiomedical research. Interwoven advancesin genetics, comparative genomics, high-throughput biochemistry and bioinformatics

NATURE | VOL 422 | 24 APRIL 2003 | www.nature.com/nature 835

are providing biologists with amarkedly improved repertoire of researchtools that will allow the functioning of organ-

isms in health and disease to be analysed andcomprehended at an unprecedented level ofmolecular detail. Genome sequences, thebounded sets of information that guide bio-logical development and function, lie at theheart of this revolution. In short, genomicshas become a central and cohesive disciplineof biomedical research.

The practical consequences of the emer-gence of this new field are widely apparent.Identification of the genes responsible forhuman mendelian diseases,once a herculeantask requiring large research teams, manyyears of hard work, and an uncertain out-come, can now be routinely accomplished

in a few weeks by a single graduate studentwith access to DNA samples and associatedphenotypes, an Internet connection to thepublic genome databases, a thermal cyclerand a DNA-sequencing machine. With the

recent publication of a draft sequence ofthe mouse genome11, identification ofthe mutations underlying a vast numberof interesting mouse phenotypes has simi-larly been greatly simplified. Comparison

of the human and mouse sequencesshows that the proportion of themammalian genome under evolu-

tionary selection is more than twice thatpreviously assumed.

Our ability to explore genome function isincreasing in specificity as each subsequent

genome is sequenced. Microarraytechnologies have catapulted manylaborator ies from studying the expres-sion of one or two genes in a monthto studying the expression of tens of

thousands of genes in a single after-noon12. Clinical opportunitiesfor gene-based pre-symptomaticprediction of illness and adversedrug response are emerging at a

rapid pace, and the therapeuticpromise of genomics has usheredin an exciting phase of expansion

and exploration in the commercialsector13.The investment of the HGP in

studying the ethical, legal and socialimplications of these scientific advances

has created a talented cohort of scholars inethics, law, social science, clinical research,theology and public policy, and has alreadyresulted in substantial increases in publicawareness and the introduction of significant(but still incomplete) protections againstmisuses such as genetic discrimination (see

www.genome.gov/PolicyEthics).These accomplishments fulfil the expan-sive vision articulated in the 1988 report ofthe National Research Council,Mapping andSequencing the Human Genome14. The suc-cessful completion of the HGP this year thusrepresents an opportunity to look forwardand offer a blueprint for the future ofgenomics research over the next several years.

The vision presented here addresses adifferent world from that reflected in earlierplans published in 1990,1993 and 1998 (refs1517). Those documents addressed thegoals of the 1988 report, defining detailedpaths towards the development of genome-

*Endorsed by the National Advisory Council for Human Genome

Research,whose member s are Vickie Yates Brown,David R.Burgess,

Wylie Burke,Ronald W.Davis,William M. Gelbart,Eric T.Juengst,

Bronya J.Keats,Raju Kucherlapati,Richard P. Lifton, Kim J.

Nickerson, Maynard V. Olson,Janet D.Rowley,Robert Tepper,

Robert H. Waterston and Tadataka Yamada.

A vision for the future ofgenomics researchA blueprint for the genom ic era.

2003 NaturePublishingGroup


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analysis technologies, the physical andgenetic mapping of genomes, and thesequencing of model organism genomesand, ultimately, the human genome. Now,with the effective completion of these goals,we offer a broader and still more ambitiousvision, appropriate for the true dawning ofthe genomic era. The challenge is to capital-ize on the immense potential of the HGP toimprove human health and well-being.

The articulation of a new vision is an

opportunity to explore transformative newapproaches to achieve health benefits.Although genome-based analysis methodsare rapidly permeating biomedical research,the challenge of establishing robust paths

from genomic information to improvedhuman health remains immense. Currentefforts to meet this challenge are largelyorganized around the study of specific dis-eases, as exemplified by the missions of thedisease-oriented institutes at the US Nation-al Institutes of Health (NIH, www.nih.gov)and numerous national and internationalgovernmental and charitable organizationsthat support medical research.The NationalHuman Genome Research Institute

(NHGRI), in budget terms a rather small(less than 2%) component of the NIH, willwork closely with all these organizations inexploring and supporting these biomedicalresearch capabilities. In addition, we envi-

sion a more direct role for both the extra-mural and intramural programmes of theNHGRI in bringing a genomic approach tothe translation of genomic sequence infor-mation into health benefits.

The NHGRI brings two unique assets tothis challenge.First, it has close ties to a scien-tific community whose direct role over thepast 13 years in bringing about the genomic

revolution provides great familiarity with itspotential to transform biomedical research.Second, the NHGRIs long-standing mission,to investigate the broadest possible implica-tions of genomics,allows unique flexibility toexplore the whole spectrum of human healthand disease from the fresh perspective ofgenome science. By engaging the energeticand interdisciplinary genomics-researchcommunity more directly in health-relatedresearch and by exploiting the NHGRIs abili-ty to pursue oppor tunities across all areas ofhuman biology, the institute seeks to partici-pate directly in translating the promises ofthe HGP into improved human health.

To fully achieve this goal, the NHGRImust also continue in its vigorous support ofanother of its vital missions the couplingof its scientific research programme withresearch into the social consequences ofincreased availability of new genetic tech-nologies and information. Translating thesuccess of the HGP into medical advancesintensifies the need for proactive efforts toensure that benefits are maximized andharms minimized in the many dimensionsofhuman experience.

A reader s guide

The vision for genomics research detailedhere is the outcome of almost two years ofintense discussions with hundreds of scien-tists and members ofthe public,in more thana dozen workshops and numerous individ-ual consultations (see www.genome.gov/About/Planning). The vision is formulatedinto three major themes genomics to biol-ogy, genomics to health, and genomics tosociety and six crosscutting elements.

We envisage the themes as three floorsof a building, firmly resting on the founda-tion of the HGP (Figure 2). For each theme,we present a series of grand challenges,in the

spirit of the proposals put forward for math-ematics by David Hilbert at the turn of thetwentieth centur y18. These grand challengesare intended to be bold, ambitious researchtargets for the scientific community. Somecan be planned on specific timescales,othersare less amenable to that level of precision.We list the grand challenges in an order thatmakes logical sense,not representing priori-ty. The challenges are broad in sweep, notparochial some can be led by the NHGRIalone, whereas others will be best pursuedin partnership with other organizations.Below, we clarify areas in which the NHGRIintends to play a leading role.

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One of the key and distinctive

objectives of the Human Genome

Project (HGP) has been the generation

of large, publicly available,

comprehensive sets of reagents and

data (scientific resources or infrastructure) that,

along with other new, powerful technologies,

comprise a toolkit for genomics-based research.

Genomic maps and sequences are the most

obvious examples. Others include databases of

sequence variation, clone libraries and collections

of anonymous cell lines. The continued generation

of such resources is critical, in particular:

x Genome sequences of key mammals,

vertebrates, chordates, and invertebrates

x Comprehensive reference sets of coding

sequences from key species in various formats,

for example, full-length cDNA sequences and

corresponding clones, oligonucleotide primers,

and microarrays

x Comprehensive collections of knockouts and

knock-downs of all genes in selected animals to

accelerate the development of models of disease

x Comprehensive reference sets of proteins from

key species in various formats, for example in

expression vectors, with affinity tags and spotted

onto protein chips

x Comprehensive sets of protein affinity reagents

x Databases that integrate sequences with

curated information and other large data sets, as

well as tools for effective mining of the data

x Cohort populations for studies designed to

identify genetic contributors to health and to

assess the effect of individual gene variants on

disease risk, including a healthy cohort

x Large libraries of small molecules, together

with robotic methods to screen them and

access to medicinal chemistry for follow-up,

to provide investigators easy and affordable

access to these tools

BOX 1 Resources

Fig 2 The future of genomics rests on the foundation of the Human Genome Project.



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probably contains the bulk of the regulatoryinformation controlling the expression ofthe approximately 30,000 protein-codinggenes, and myriad other functional ele-ments, such as non-protein-coding genesand the sequence determinants of chromo-some dynamics.Even less is known about thefunction of the roughly half of the genomethat consists ofhighly repetitive sequences orof the remaining non-coding,non-repetitiveDNA.

The next phase of genomics is to cata-logue, characterize and comprehend theentire set of functional elements encoded inthe human and other genomes. Compiling

this genome parts list will be an immensechallenge. Well-known classes of functional

elements,such as protein-coding sequences,still cannot be accurately predicted fromsequence information alone. Other t ypes ofknown functional sequences, such as geneticregulatory elements, are even less wellunderstood;undoubtedly new types remainto be defined, so we must be ready to investi-gate novel, perhaps unexpected, ways inwhich DNA sequence can confer function.

Similarly, a better understanding of epi-genetic changes (for example, methylationand chromatin remodelling) is needed tocomprehend the full repertoire of ways inwhich DNA can encode information.

Comparison of genome sequences fromevolutionarily diverse species has emerged asa powerful tool for identifying functionallyimportant genomic elements. Initial analysesof available vertebrate genome sequences7,11,19

have revealed many previously undiscoveredprotein-coding sequences. Mammal-to-mammal sequence comparisons have revealedlarge numbers of homologies in non-codingregions11, few of which can be defined infunctional terms. Further comparisons ofsequences derived from multiple species,espe-cially those occupying distinct evolutionarypositions, will lead to significant refinementsin our understanding ofthe functional impor-tance of conserved sequences20. Thus, thegeneration of additional genome sequencesfrom several well-chosen species is crucial tothe functional characterization of the humangenome (Box 1). The generation of such largesequence data sets will benefit from furtheradvances in sequencing technology that yieldsignificant cost reductions (Box 2). The studyof sequence variation within species will also

be important in defining the functional natureofsome sequences (see Grand Challenge I-3).

The six critically important crosscuttingelements are relevant to all three thematicareas.They are: resources (Box 1); technolo-gy development (Box 2); computationalbiology (Box 3); training (Box 4); ethical,legal and social implications (ELSI, Box 5);and education (Box 6). We also stress thecritical importance of early, unfetteredaccess to genomic data in achieving maxi-

mum public benefit. Finally, we propose aseries ofquantum leaps, achievements thatwould lead to substantial advances ingenomics research and its applications tomedicine. Some of these may seem overlybold,but no laws ofphysics need to be violat-ed to achieve them. Such leaps would haveprofound implications, just as the dreams ofthe mid-1980s about the complete sequenceof the human genome have been realized inthe accomplishments now being celebrated.

I Genomics to biologyElucidating the structureand function of genomesThe broadly available genome sequences ofhuman and a select set of additional organ-isms represent foundational informationfor biology and biomedicine. Embeddedwithin this as-yet poorly understood codeare the genetic instructions for the entirerepertoire of cellular components, knowl-edge of which is needed to unravel thecomplexities ofbiological systems.Elucidat-ing the structure of genomes and identifyingthe function of the myriad encoded elementswill allow connections to be made betweengenomics and biology and will, in turn ,accelerate the exploration of all realms ofthe

biological sciences.For this,new conceptual and technologi-

cal approaches will be needed to:x Develop a comprehensive and com-

prehensible catalogue of all of thecomponents encoded in the humangenome.

x Determine how the genome-encodedcomponents function in an integratedmanner to perform cellular andorganismal functions.

x Understand how genomes change andtake on new functional roles.

Grand Challenge I-1 Comprehensivelyidentify the structural and functionalcomponents encoded in the humangenomeAlthough DNA is relatively simple and wellunderstood chemically,the human genomesstructure is extraordinarily complex and itsfunction is poorly understood.Only 12% ofits bases encode proteins7, and the full com-plement of protein-coding sequences stillremains to be established. A roughly equiva-lent amount of the non-coding portion ofthe genome is under active selection11, sug-gesting that it is also functionally impor tant ,yet vanishingly little is known about it. It

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The Human Genome Project was

aided by several breakthrough

technological developments, including

Sanger DNA sequencing and its

automation, DNA-based genetic

markers, large-insert cloning systems and the

polymerase chain reaction. During the project,

these methods were scaled up and made more

efficient by evolutionary advances, such as

automation and miniaturization. New

technologies, including capillary-based

sequencing and methods for genotyping single-

nucleotide polymorphisms, have recently been

introduced, leading to further improvements in

capacity for genomic analyses. Even newer

approaches, such as nanotechnology and

microfluidics, are being developed, and hold great

promise, but further advances are still needed.

Some examples are:

x Sequencing and genotyping technologies to

reduce costs further and increase access to a

wider range of investigators

x Identification and validation of functional

elements that do not encode protein

x In vivo, real-time monitoring of gene expression

and the localization, specificity, modification and

activity/kinetics of gene products in all relevant

cell types

x Modulation of expression of all gene products

using, for example, large-scale mutagenesis,

small-molecule inhibitors and knock-down

approaches (such as RNA-mediated inhibition)

x Monitoring of the absolute abundance of

any protein (including membrane proteins,

proteins at low abundance and all modified

forms) in any cell

x Improved imaging methods that allow non-

invasive molecular phenotyping

x Correlating genetic variation to human health

and disease using haplotype information or

comprehensive variation information

x Laboratory-based phenotyping, including the

use of protein affinity reagents, proteomic

approaches and analysis of gene expression

x Linking molecular profiles to b iology,

particularly pathway biology to disease

BOX 2 Technology development



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Establishing a true understanding ofhoworganized molecular pathways and networksgive rise to normal and pathological cellularand organismal phenotypes will requiremore than large,experimentally derived datasets. Once again, computational investiga-tion will be essential (Box 3), and there willbe a greatly increased need for the collection,storage and display of the data in robust

databases. By modelling specific pathwaysand networks, predicting how they affectphenotype, testing hypotheses derived fromthese models and refining the models basedon new experimental data, it should bepossible to understand more completely thedifference between a bag of moleculesand afunctioning biological system.

Grand Challenge I-3 Develop a detailedunderstanding of the heritable variation inthe human genomeGenetics seeks to correlate variation in DNAsequence with phenotypic differences(traits). The greatest advances in humangenetics have been made for t raits associatedwith variation in a single gene. But mostphenotypes, including common diseasesand variable responses to pharmacologicalagents, have a more complex origin, involv-ing the interplay between multiple geneticfactors (genes and their products) and non-genetic factors (environmental influences).Unravelling such complexity will requireboth a complete description of the geneticvariation in the human genome and thedevelopment of analytical tools for usingthat information to understand the geneticbasis of disease.

Establishing a catalogue of all commonvariants in the human population, includingsingle-nucleotide polymorphisms (SNPs),small deletions and insertions, and otherstructural differences, began in earnestseveral years ago. Many SNPs have beenidentified28, and most are publicly available(www.ncbi.nlm.nih.gov/SNP). A publiccollaboration, the International HapMapProject (www.genome.gov/Pages/Research/HapMap), was formed in 2002 to character-ize the patterns of linkage disequilibriumand haplotypes across the human genomeand to identify subsets of SNPs that capture

most of the information about these patternsof genetic variation to enable large-scalegenetic association studies.To reach fruit ion,such studies need more robust experimental(Box 2) and computational (Box 3) methodsthat use this new knowledge of humanhaplotype structure29.

A comprehensive understanding ofgeneticvariation, both in humans and in modelorganisms,would facilitate studies to establishrelationships between genotype and biologi-cal function. The study of particular variantsand how they affect the functioning ofspecificproteins and protein pathways will yieldimportant new insights about physiological

processes in normal and disease states. Anenhanced ability to incorporate informationabout genetic variation into human geneticstudies would usher in a new era for investigat-ing the genetic bases of human disease anddrug response (see Grand Challenge II-1).

Grand Challenge I-4 Understandevolutionary variation across species andthe mechanisms underlying itThe genome is a dynamic structure,continu-ally subjected to modification by the forcesof evolution. The genomic variation seenin humans represents only a small glimpsethrough the larger window of evolution,

where hundreds of millions of years of trial-and-error efforts have created todays bio-

sphere ofanimal,plant and microbial species.A complete elucidation of genome functionrequires a parallel understanding of thesequence differences across species and thefundamental processes that have sculptedtheir genomes into the modern-day forms.

The study of inter-species sequence com-parisons is important for identifying func-tional elements in the genome (see Grand

Challenge I-1). Beyond this illuminatingrole, determining the sequence differencesbetween species will provide insight intothe distinct anatomical, physiological anddevelopmental features of different organ-isms,will help to define the genetic basis forspeciation and will facilitate the characteri-zation of mutational processes. This lastpoint deserves particular attention, becausemutation both drives long-term evolution-ary change and is the underlying cause ofinherited disease. The recent finding thatmutation rates vary widely across the mam-malian genome11 raises numerous questionsabout the molecular basis for these evolu-tionary changes.At present, our understand-ing of DNA mutation and repair, includingthe important role of environmental factors,is limited.

Genomics will provide the ability to sub-stantively advance insight into evolutionaryvariation, which will, in turn, yield newinsights into the dynamic nature of genomesin a broader evolutionary framework.

Grand Challenge I-5 Develop policyoptions that facilitate the widespread useof genome information in both researchand clinical settings

Realization of the opportunities provided bygenomics depends on effective access to the

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Meeting the scientific, medical and

social/ethical challenges now facing

genomics will require scientists,

clinicians and scholars with the skills

to understand biological systems and

to use that information effectively for the benefit

of humankind. Adequate training capacity will be

required to address the following needs:

x Computational skills As biomedical research

is becoming increasingly data intensive,

computational capability is increasingly becoming

a critical skill.

x Interdisciplinary skills Although a good start

has been made, expanded interactions will be

required between the sciences (biology, computer

science, physics, mathematics, statistics,

chemistry and engineering), between the basic

and the clinical sciences, and between the life

sciences, the social sciences and the humanities.

Such interactions will be needed at the individual

level (scientists, clinicians and scholars will need

to be able to bring relevant issues, concerns and

capabilities from different disciplines to bear on

their specific research efforts), at a collaborative

level (researchers will need to be able to

participate effectively in interdisciplinary research

collaborations that bring biology together with

many other disciplines) and at the disciplinary

level (new disciplines will need to emerge at the

interfaces between the traditional d isciplines).

x Different perspectives Individuals from

minority or disadvantaged populations are

significantly under-represented as both

researchers and participants in genomics

research. This regrettable circumstance deprives

the field of the best and brightest from all

backgrounds, narrows the field of questions

asked, can lessen sensitivity to cultural concerns

in implementing research protocols, and

compromises the overall effectiveness of the

research. Genomics can learn from successful

efforts in training individuals from under-

represented populations in other areas of science

and health (see, for example,

www.genome.gov/Pages/Grants/Policies/

ActionPlanGuide).

BOX 4 Training



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information (such as data about genes,genevariants, haplotypes, protein structures,small molecules and computational models)by a wide range of potential users, includingresearchers, commercial enterpr ises, health-care providers, patients and the public.Researchers themselves need maximumaccess to the data as soon as possible (seeData release,below). Use ofthe in formation

for the development of therapeutic andother products necessarily entails considera-tion of the complex issues of intellectualproperty (for example,patenting and licens-ing) and commercialization. The intellectualproperty practices, laws and regulations thataffect genomics must adhere to the principleof maximizing public benefit, but must alsobe consistent with more general and longer-established intellectual property principles.Further, because genome research is global,international treaties, laws, regulations,practices, belief systems and cultures alsocome into play.

Without commercialization, most diag-nostic and therapeutic advances will notreach the clinical setting, where they canbenefit patients. Thus, we need to developpolicy options for data access and for patent-ing, licensing and other intellectual propertyissues to facilitate the dissemination ofgenomics data.

II Genomics to healthTranslating genome-based knowledgeinto health benefitsThe sequencing of the human genome,along with other recent and expectedachievements in genomics, provides an

unparalleled opportunity to advance ourunderstanding of the role of genetic factorsin human health and disease, to allowmore precise definition of the non-geneticfactors involved, and to apply this insightrapidly to the prevention, diagnosis and

treatment of disease. The report by the USNational Research Council that originallyenvisioned the HGP was explicit in its expec-tation that the human genome sequencewould lead to improvements in humanhealth, and subsequent five-year plansreaffirmed this view1517. But how this willhappen has been less clearly articulated.With the completion of the original goalsof the HGP, the time is right to developand apply large-scale genomic strategiesto empower improvements in humanhealth, while anticipating and avoidingpotential harm.

Such strategies should enable the research

community to achieve the following:x Identify genes and pathways with a

role in health and disease, and deter-mine how they interact with environ-mental factors.

x Develop,evaluate and apply genome-

based diagnostic methods for the pre-diction of susceptibility to disease,theprediction of drug response,the earlydetection of illness and the accuratemolecular classification of disease.

x Develop and deploy methods thatcatalyse the translation of genomicinformation into therapeutic advances.

Grand Challenge II-1 Develop robuststrategies for identifying the geneticcontributions to disease and drug responseFor common diseases,the interplay of multi-ple genes and multiple non-genetic factors,not a single allele, usually dictates diseasesusceptibility and response to treatments.Deciphering the role of genes in humanhealth and disease is a formidable problemfor many reasons, including impedimentsto defining biologically valid phenotypes,challenges in identifying and quantifyingenvironmental exposures, technologicalobstacles to generating sufficient and usefulgenotypic information, and the difficultiesof studying humans.Yet this problem can besolved. Vigorous development of cross-cutting genomic tools to catalyse advancesin understanding the genetics of commondisease and in pharmacogenomics is needed.Prominent among these will be a detailedhaplotype map of the human genome(see Grand Challenge I-3) that can be usedfor whole-genome association studies ofall diseases in all populations, as well asfurther advances in sequencing andgenotyping technology to make such studiesfeasible (see Quantum leaps,below).

More efficient strategies for detecting

rare alleles involved in common diseaseare also needed, as the hypothesis that allelesthat increase risk for common diseases arethemselves common30 will probably not beuniversally true.Computational and experi-mental methods to detect genegeneand geneenvironment interactions, as wellas methods allowing interfacing of a varietyof relevant databases, are also required(Box 3). By obtaining unbiased assessmentsof the relative disease risk that part iculargene variants contribute,a large longitudinalpopulation-based cohort study,with collec-tion of extensive clinical information and

ongoing follow-up, would be profoundlyvaluable to the study of all common diseases(Box 1). Already, such projects as theUK Biobank (www.ukbiobank.ac.uk),the Marshfield Clinics Personalized Medi-cine Research Project (www.mfldclin.edu/pmrp) and the Estonian Genome Project(www.geenivaramu.ee) seek to provide suchresources. But if the multiple populationgroups in the United States and elsewhere inthe world are to benefit fully and fairly fromsuch research (see Grand Challenge II-6), alarge population-based cohort study thatincludes full representation of minoritypopulations is also needed.

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Todays genomics research and

applications rest on more than a

decade of valuable investigation into

their ethical, legal and social

implications. As the application of

genomics to health increases along with its

social impact, it becomes ever more important

to expand on this work. There is an increasing

need for focused ELSI research that d irectly

informs policies and practices. One can

envisage a flowering of translational ELSI

research that builds on the knowledge

gained from prior and forthcoming basic

ELSI research, which would provide

knowledge for d irect use by researchers,

clinicians, policy-makers and the public.

Examples include:

x The development of models of genomics

research that use attention to these ELSI issues

for enhancing the research, rather than viewing

such issues as impediments

x The continued development of appropriate

and effective genomics research methods and

policies that promote the highest levels of

science and of protecting human subjects

x The establishment of crosscutting tools,

analogous to the publicly accessible genomic

maps and sequence databases that have

accelerated other genomics research (examples

of such tools might include searchable databases

of genomic legislation and policies from around

the world, or studies of ELSI aspects of

introducing clinical genetic tests)

x The evaluation of new genetic and genomic

tests and technologies, and effective oversight

of their implementation, to ensure that only

those with confirmed clinical validity are used for

patient care

BOX 5 Ethical, legal and social implications (ELSI)



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Grand Challenge II-2 Develop strategiesto identify gene variants that contribute togood health and resistance to diseaseMost human genetic research has tradition-ally focused on identifying genes that pre-dispose to illness. A relatively unexplored,but important , area of research focuses onthe role of genetic factors in maintaininggood health. Genomics will facilitate further

understanding of this aspect ofhuman biol-ogy and allow the identification of genevariants that are important for the mainten-ance of health,part icularly in the presence ofknown environmental risk factors.One use-ful research resource would be a healthycohort, a large epidemiologically robustgroup of individuals (Box 1) with unusuallygood health, who could be compared withcohorts of individuals with diseases and whocould also be intensively studied to revealalleles protective for conditions such as dia-betes, cancer, heart disease and Alzheimersdisease.Another promising approach wouldbe rigorous examination of genetic variantsin individuals at high risk for specific dis-eases who do not develop them, such assedentary,obese smokers without heart dis-ease or individuals withHNPCCmutationswho do not develop colon cancer.

Grand Challenge II-3 Develop genome-based approaches to prediction of diseasesusceptibility and drug response, earlydetection of illness, and moleculartaxonomy of disease statesThe discovery of variants that affect risk fordisease could potentially be used in individ-ualized preventive medicine including

diet, exercise, lifestyle and pharmaceuticalintervention to maximize the likelihoodof staying well.For example, the discovery ofvariants that correlate with successful out-comes of drug therapy, or with unfortunateside effects, could potentially be rapidlytranslated into clinical practice.Turning thisvision into reality will require the following:(1) unbiased determination of the riskassociated with a particular gene variant,often overestimated in initial studies31;(2) technological advances to reduce the costof genotyping (Box 2; see Quantum leaps,below); (3) research on whether th is kind of

personalized genomic information willactually alter health behaviours (see GrandChallenge II-5); (4) oversight of the imple-mentation of genetic tests to ensure that onlythose with demonstrated clinical validity areapplied outside of the research setting (Box5); and (5) education of healthcare profes-sionals and the public to be well-informedparticipants in this new form of preventivemedicine (Box 6).

The time is right for a focused effort tounderstand, and potentially to reclassify, allhuman illnesses on the basis of detailed mol-ecular characterization. Systematic analysesof somatic mutations, epigenetic modifica-

tions, gene expression, protein expressionand protein modification should allow thedefinition of a new molecular taxonomy ofillness, which would replace our present,largely empirical,classification schemes andadvance both disease prevention and treat-ment.The reclassification of neuromusculardiseases32 and certain types of cancer33 pro-vides striking initial examples, but manymore such applications are possible.

Such a molecular taxonomy would be thebasis for the development of better methodsfor the early detection of disease,which oftenallows more effective and less costly treat-ments. Genomics and other large-scale

approaches to biology offer the potential for

developing new tools to detect many diseasesearlier than is currently feasible. Suchsentinelmethods might include analysis ofgene expression in circulating leukocytes,proteomic analysis of body fluids, andadvanced molecular analysis of tissue biop-sies. An example would be the analysis ofgene expression in peripheral blood leuko-cytes to predict drug response. A focused

effort to use a genomic approach to charac-terize serum proteins exhaustively in healthand disease might also be highly rewarding.

Grand Challenge II-4 Use newunderstanding of genes and pathways todevelop powerful new therapeuticapproaches to diseasePharmaceuticals on the market target fewerthan 500 human gene products34. Eventhough not all of the 30,000 or so humanprotein-coding genes7 will have productstargetable for drug development, this sug-gests that there is an enormous untappedpool of human gene-based targets for thera-peutic intervention. In addition, the newunderstanding of biological pathways pro-vided by genomics (see Grand Challenge I-2)should contribute even more fundamentallyto therapeutic design.

The information needed to determinethe therapeutic potential of a gene generallyoverlaps heavily with the information thatreveals its function . The success of imatinibmesylate (Gleevec), an inhibitor of the BCR-ABL tyrosine kinase, in treating chronicmyelogenous leukaemia relied on a detailedmolecular understanding of the diseasesgenetic cause35. This example offers promise

that therapies based on genomic informa-

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Marked health improvements from

integrating genomics into individual and

public health care depend on the

effective education of health

professionals and the public about the

interplay of genetic and environmental factors in

health and disease. Health professionals must be

knowledgeable about genomics to use the

outcomes of genomics research effectively. The

public must be knowledgeable to make informed

decisions about participation in genomics research

and to incorporate the findings of such research

into their own health care. Both groups must be

knowledgeable to engage profitably in discussion

and decision-making about the societal

implications of genomics.

Promising models for genomics and

genetics education exist (see, for example,

www.nchpeg.org), but they must be expanded and

new models developed. We have entered a unique

educable era regarding genomics; health

professionals and the public are increasingly

interested in learning about genomics, but its

widespread application to health is still several

years away. For genomics-based health care to be

maximally effective once it is widely feasible, and

for members of society to make the best decisions

about the uses of genomics, we must take

advantage now of this unique opportunity to

increase understanding. Some examples are:

x Health professionals vary, both individually and

by discipline, in the amount and type of genomics

education that they require. So multiple models of

effective genomics-related education are needed.

x Print, web and video educational products that

the public can consume when actively seeking

genomic information should be created and made

easily available.

x The media are crucial sources of information

about genomics and its societal implications.

Initiatives to provide the media with greater

understanding of genomics are needed.

x High-school students will be both the users of

genomic information and the genomics researchers

of the future. Especially as they educate all sectors

of society, high-school educators need information

and materials about genomics and its implications

for society, to use in their classrooms.

BOX 6 Education



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tion will be part icularly effective. GrandChallenge I-1 describes the functionationofthe genome, which will increasingly be thecritical first step in the development of newtherapeutics.But stimulating basic scientiststo approach biomedical problems with agenomic attitude is not enough.A therapeu-tic mindset, lacking in much of academicbiomedical research and training, must be

explicitly encouraged, and tools developedand provided for its implementation.

A particularly promising example of thegene-based approach to therapeutics is theapplication of chemical genomics25. Thisstrategy uses libraries of small molecules(natural compounds, aptamers or theproducts of combinatorial chemistry) andhigh-throughput screening to advanceunderstanding of biological pathways andto identify compounds that act as positiveor negative regulators of individual geneproducts, pathways or cellular phenotypes.Although the pharmaceutical industryapplies this approach widely as the first stepin drug development, few academic investi-gators have access to this methodology or arefamiliar with its use.

Providing such access more broadly,through one or more centralized facilities,could lead to the discovery of a host of usefulprobes for biological pathways that wouldserve as new reagents for basic researchand/or starting points for the developmentof new therapeutic agents (the hits fromsuch library screens will generally requiremedicinal chemistry modifications to yieldtherapeutically usable compounds).

Also needed are new, more powerful

technologies for generating deep molecularlibraries, especially ones tagged to allow theready determination of precise moleculartargets. A centralized database of screeningresults should lead to further importantbiological insights. Generating molecularprobes for exploring the basic biology ofhealth and disease in academic laboratorieswould not supplant the major role of bio-pharmaceutical companies in drug develop-ment, but could contribute to the start of thedrug development pipeline. The privatesector would doubtless find many of thesemolecular probes of interest for further

exploration through optimization by medic-inal chemistry, target validation, lead com-pound identification, toxicological studiesand,ultimately,clinical trials.

Academic pursuit of this first step in drugdevelopment could be particularly valuablefor the many rare mendelian diseases, inwhich often the gene defect is known but thesmall market size limits the pr ivate sectorsmotivation to shoulder the expense ofeffective pharmaceutical development. Suchtranslational research in academic laborato-ries, combined with incentives such as theUS Orphan Drug Act, could profoundlyincrease the availability of effective treat-

ments for rare genetic diseases in the nextdecade. Further, the development of thera-peutic approaches to single-gene disordersmight provide valuable insights into apply-ing genomics to reveal the biology of morecommon disorders and developing moreeffective treatments for them (in the waythat, for example,the search for compoundsthat target the presenilins has led to generaltherapeutic strategies for late-onsetAlzheimers disease36).

Grand Challenge II-5 Investigate howgenetic risk information is conveyed inclinical settings, how that information

influences health strategies andbehaviours, and how these affect healthoutcomes and costsUnderstanding how genetic factors affecthealth is often cited as a major goal ofgenomics, on the assumption that applyingsuch understanding in the clinical setting willimprove health. But this assumption actuallyrests on relatively few examples and data, andmore research is needed to provide sufficientguidance about how to use genomic informa-tion optimally for improving individual orpublic health.

Theoretically, the steps by which genetic

risk information would lead to improvedhealth are: (1) an individual obtainsgenome-based information about his/herown health risks;(2) the individual uses thisinformation to develop an individualized

prevention or treatment plan; (3) the indi-vidual implements that plan; (4) this leads toimproved health;and (5) healthcare costs arereduced. Scrutiny of these assumptions isneeded, both to test them and to determinehow each step could best be accomplished indifferent clinical settings.

Research is also required that criticallyevaluates new genetic tests and interventions

in terms of parameters such as benefits,access and cost. Such research should beinterdisciplinary and use the tools andexpertise of many fields, includinggenomics, health education, health behav-iour research, health outcomes research,healthcare delivery analysis, and healthcareeconomics.Some of these fields have histori-cally paid little attention to genomics, buthigh-quality research of this sort could pro-vide important guidance in clinical decision-making as the work of several disciplineshas already been helpful in caring for peoplewith an increased risk of colon cancer as aresult of mutations in FAPorHNPCC37.

Grand Challenge II-6 Develop genome-based tools that improve the health of allDisparities in health status constitute a signif-icant global issue, but can genome-basedapproaches to health and disease help toreduce this problem? Social and other envi-ronmental factors are major contributors tohealth disparities; indeed, some would ques-tion whether heritable factors have anysignificant role.But population differences inallele frequencies for some disease-associatedvariants could be a contributing factor to cer-tain disparities in health status, so incorporat-

ing this information into preventive and/orpublic-health strategies would be beneficial.Research is needed to understand the rela-tionship between genomics and health dis-parities by rigorously evaluating the diversecontributions of socioeconomic status,culture, discrimination, health behaviours,diet,environmental exposures and genetics.

It is also important to explore applicationsof genomics in the improvement of health inthe developing world (www3.who.int/whosis/genomics/genomics_report.cfm),where bothhuman and non-human genomics will playsignificant roles.If we take malaria as an exam-

ple,a better understanding of human geneticfactors that influence susceptibility andresponse to the disease, and to the drugs usedto treat it, could have a significant globalimpact.So too could a better understanding ofthe malarial parasite itselfand of its mosquitovector, which the recently reported genomesequences38,39 should provide. It will be neces-sary to determine the appropriate roles ofgovernmental and non-governmental organi-zations, academic institutions, industry andindividuals to ensure that genomics producesclinical benefits for resource-poor nations,and is used to produce robust local researchexpertise.

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To ensure that genomics research benefitsall, it will be critical to examine howgenomics-based health care is accessed andused. What are the barriers to equitableaccess,and how can they be removed? This isrelevant not only in resource-poor nations,but also in wealthier countries where seg-ments ofsociety,such as indigenous popula-tions, the uninsured, or rural and inner city

communities,have tradit ionally not receivedadequate health care.

III Genomics to societyPromoting the use of genomics tomaximize benefits and minimize harmsGenomics has been at the forefront of givingserious attention, through scholarly researchand policy discussions, to the impact of sci-ence and technology on society. Althoughthe major benefits to be realized fromgenomics are in the area of health, asdescribed above, genomics can also con-tribute to other aspects of society. Just as theHGP and related developments havespawned new areas of research in basic biol-ogy and in health, they have also createdopportunities for research on social issues,even to the extent of understanding morefully how we define ourselves and each other.

In the next few years,society must not onlycontinue to grapple with numerous questionsraised by genomics, but must also formulateand implement policies to address many ofthem. Unless research provides reliable dataand rigorous approaches on which to basesuch decisions, those policies will be ill-informed and could potentially compromiseus all. To be successful, this research must

encompass both basic investigations thatdevelop conceptual tools and shared vocabu-laries, and more applied, translationalprojects that use these tools to explore anddefine appropriate public-policy options thatincorporate diverse points of view.

As it has in the past, such research willcontinue to have important ramificationsfor all three major themes of the vision pre-sented here. We now address research thatfocuses on society itself,more than on biolo-gy or health. Such efforts should enable theresearch community to:x Analyse the impact of genomics on

concepts of race, ethnicity, kinship,individual and group identity, health,disease and normality for traits andbehaviours.

x Define policy options,and their poten-tial consequences, for the use of gen-omic information and for the ethicalboundaries around genomics research.

Grand Challenge III-1 Develop policyoptions for the uses of genomics inmedical and non-medical settingsSurveys have repeatedly shown that thepublic is highly interested in the conceptthat personal genetic information might

guide them to better health, but is deeplyconcerned about potential misuses of thatinformation (see www.publicagenda.org/issues/pcc_detail.cfm?issue_type=medical_research&list=7). Topping the list of con-cerns is the potential for discrimination inhealth insurance and employment.A signifi-cant amount of research on this issue hasbeen done40, policy options have beenpublished4143, and many US states havenow passed anti-discrimination legislation(see www.genome.gov/Pages/PolicyEthics/Leg/StateIns and www.genome.gov/Pages/PolicyEthics/Leg/StateEmploy). The USEqual Employment Opportunity Commis-

sion has ruled that the Americans with Dis-abilities Act should apply to discriminationbased on predictive genetic information44,but the legal status of that construct remainsin some doubt. Although an executive orderprotects US government employees againstgenetic discrimination, this does not apply toother workers. Thus, many observers haveconcluded that effective federal legislation isneeded, and the US Congress is currentlyconsidering such a law.

Making certain that genetic tests offered tothe public have established clinical validityand usefulness must be a priority for future

research and policy making. In the UnitedStates,the Secretarys Advisory Committee onGenetic Testing extensively reviewed this areaand concluded that further oversight is need-ed,asking the Food and Drug Administration

to review new predictive genetic tests priorto marketing (www4.od.nih.gov/oba/sacgt/reports/oversight_report.pdf). That recom-mendation has not yet been acted on; mean-while,numerous websites offering unvalidat-ed genetic tests directly to the public, oftencombined with the sale ofnutraceuticalsandother products of highly questionable value,are proliferating.

Many issues currently swirl around theproper conduct of genetic research involvinghuman subjects, and further work is neededto achieve a satisfactory balance between theprotection of research participants fromharm and the ability to conduct clinicalresearch that benefits society as a whole.Mucheffort has gone into developing appropriateguidelines for the use of stored tissue speci-mens (www.georgetown.edu/research/nrcbl/nbac/hbm.pdf),for community consultationwhen conducting genetic research with iden-tifiable populations (www.nigms.nih.gov/news/reports/community_consultation.html#exec),and for the consent of non-examinedfamily members when conducting pedigreeresearch (www.nih.gov/sigs/bioethics/nih_third_party_rec.html), but confusion stillremains for many investigators and institu-tional review boards.

The use of genomic information is notlimited to the arenas of biology and of health,and further research and development of pol-icy options is also needed for the many otherapplications of such information. The arrayof additional users is likely to include the life,disability and long-term care insuranceindustr ies, the legal system, the military,edu-cational institutions and adoption agencies.

Although some of the research informing themedical uses of genomics will be useful inbroader settings, dedicated research outsidethe healthcare sphere is needed to explore thepublic values that apply to uses of genomicsother than for health care and their relation-ship to specific contextual applications. Forexample,should genetic information on pre-disposition to hyperactivity be available inthe future to school officials? Or shouldgenetic information about behavioural traitsbe admissible in criminal or civil proceed-ings? Genomics also provides greater oppor-tunity to understand ancestral origins of

populations and individuals, which raisesissues such as whether genetic informationshould be used for defining membership in aminority group.

Because uses of genomics outside thehealthcare setting will involve a significantlybroader community of stakeholders, bothresearch and policy development in this areamust involve individuals and organizationsbesides those involved in the medical applica-tions of genomics. But many of the sameperspectives essential to research and policydevelopment for the medical uses ofgenomicsare also essential. Both the potential users ofnon-medical applications ofgenomics and the

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public need education to understand betterthe nature and limits ofgenomic information(Box 6) and to grasp the ethical,legal and socialimplications of its uses outside health care(Box 5).

Grand Challenge III-2 Understand therelationships between genomics, race andethnicity, and the consequences of

uncovering these relationshipsRace is a largely non-biological concept con-founded by misunderstanding and a longhistory of prejudice. The relationship ofgenomics to the concepts of race and ethni-city has to be considered within complexhistorical and social contexts.

Most variation in the genome is sharedbetween all populations, but certain allelesare more frequent in some populations thanin others, largely as a result of history andgeography.Use of genetic data to define racialgroups, or of racial categories to classify bio-logical traits, is prone to misinterpretation.To minimize such misinterpretation, the bio-logical and sociocultural factors that inter-relate genetics with constructs of race andethnicity need to be better understood andcommunicated within the next few years.

This will require research on how differ-ent individuals and cultures conceive of race,ethnicity, group identity and self-identity,and what role they believe genes or otherbiological factors have. It will also require acritical examination of how the scientificcommunity understands and uses these con-cepts in designing research and presentingfindings,and of how the media report these.Also necessary is widespread education

about the biological meaning and limita-tions of research findings in this area (Box 6),and the formulation and adoption ofpublic-policy options that protect againstgenomics-based discrimination or maltreat-ment (see Grand Challenge III-1).

Grand Challenge III-3 Understand theconsequences of uncovering the genomiccontributions to human traits andbehavioursGenes influence not only health and disease,but also human traits and behaviours. Sci-ence is only beginning to unravel the compli-

cated pathways that underlie such attributesas handedness, cognition, diurnal rhythmsand various behavioural characteristics.Toooften, research in behavioural genetics,suchas that regarding sexual orientation or in tel-ligence, has been poorly designed and itsfindings have been communicated in a waythat oversimplifies and overstates the role ofgenetic factors.This has caused serious prob-lems for those who have been stigmatized bythe suggestion that alleles associated withwhat some people perceive as negativephys-iological or behavioural traits are morefrequent in certain populations. Given thishistory and the real potential for recurrence,

it is particularly important to gather suffi-cient scientifically valid information aboutgenetic and environmental factors to pro-vide a sound understanding of the contribu-tions and interactions between genes andenvironment in these complex phenotypes.

It is also important that there be robustresearch to investigate the implications, forboth individuals and society, of uncoveringany genomic contributions that there maybe to traits and behaviours. The field ofgenomics has a responsibility to consider thesocial implications of research into thegenetic contributions to traits and behav-iours, perhaps an even greater responsibility

than in other areas where there is less ofa his-tory of misunderstanding and stigmatiza-tion. Decisions about research in this area areoften best made with input from a diversegroup of individuals and organizations.

Grand Challenge III-4 Assess how todefine the ethical boundaries for uses ofgenomicsGenetics and genomics can contribute under-standing to many areas of biology, health andlife. Some of these human applications arecontroversial,with some members of the pub-lic questioning the propriety of their scientific

exploration. Although freedom of scientificinquiry has been a cardinal feature of humanprogress, it is not unbounded. It is importantfor society to define the appropriate and inap-propriate uses of genomics. Conversations

between diverse parties based on an accurateand detailed understanding ofthe relevant sci-ence and ethical, legal and social factors willpromote the formulation and implementa-tion ofeffective policies.For instance,in repro-ductive genetic testing, it is crucial to includeperspectives from the disability community.Research should explore how different indi-viduals,cultures and religious traditions view

the ethical boundaries for the uses ofgenomics for instance,which sets ofvalues determineattitudes towards the appropriateness ofapplying genomics to such areas as reproduc-tive genetic testing,genetic enhancementandgermline gene transfer.

Implementation: the NHGRIs roleThe vision for the future of genomicspresented here is broad and deep,and its real-ization will require the efforts of many. Con-tinuation of the extensive collaborationbetween scientists and between fundingsources that characterized the HGP will beessential. Although the NHGRI intends toparticipate in all the research areas discussedhere, it will need to focus its efforts to use itsfinite resources as effectively as possible.Thus,it will take a major role in some areas, activelycollaborate in others,and have only a support-ing role in yet others.The NHGRIs prioritiesand areas ofemphasis will also evolve as mile-stones are met and new opportunities arise.

The approach that has characterizedgenomics and led to the success of the HGP an initial focus on technology develop-ment and feasibility studies, followed bypilot efforts to learn how to apply new strat-egies and technologies efficiently on a larger

scale, and then implementation of full-scaleproduction efforts will continue to be atthe heart of the NHGRIs priority-settingprocess. The following are areas of highinterest, not listed in priority order.

Large-scale production of genomic data

sets The NHGRI will continue to supportgenomic sequencing, focusing on thegenomes of mammals, vertebrates, chord-ates and invertebrates; other funders willsupport the determination of additionalgenome sequences from microbes andplants.With current technology, the NHGRI

could support the determination of asmuch as 4560 gigabases of genomic DNAsequence, or the equivalent of 1520 humangenomes,over the next five years.But as thecost ofsequencing continues to decrease,thecost/benefit ratio of sequence generationwill improve, so that the actual amount ofsequencing done will be greatly affected bythe development of improved sequencingtechnology.

The decisions about which genomes tosequence next will be based on the results ofcomparative analyses that reveal the ability ofgenomic sequences from unexplored phylo-genetic positions to inform the interpreta-

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tion of the human sequence and to provideother insights. Finally, the degree to whichany new genomic sequence is completed finished, taken to an advanced draft stage orlightly sampled will be determined bythe use for which the sequence is generated.And,ofcourse,the NHGRIs sequencing pro-gramme will maintain close contact with,and take account of the plans and output

of, other sequencing programmes, as hashappened throughout the HGP.

A second data set ready for production-level effort is the human haplotype map(HapMap). This project, a collaborationbetween the NHGRI,many other NIH insti-tutes, and four international partners, isscheduled for completion within three years.The outcome of the International HapMapProject will significantly shape the futuredirection of the NHGRIs research efforts inthe area ofgenetic variation.

Pilot-scale efforts The NHGRI has initiatedthe ENCODE Project to begin the develop-ment of the human genome parts list. Thefirst phase will address the application andimprovement of existing technologies forthe large-scale identification of codingsequences, transcription units and otherfunctional elements for which technology iscurrently available. When the results of theENCODE Project show evidence of efficacyand affordability at the pilot scale,considera-tion will be given to implementing theappropriate technologies across the entirehuman genome.

Technology development Many areas of

critical importance to the realization of thegenomics-based vision for biomedicalresearch require new technological andmethodological developments before pilotsand then large-scale approaches can beattempted. Recognizing that technologydevelopment is an expensive and high-riskundertaking, the NHGRI is neverthelesscommitted to suppor ting and fostering tech-nology development in many of these crucialareas,including the following.

DNA sequencing. There is still greatopportunity to reduce the cost and increasethe throughput of DNA sequencing, and to

make rapid, cheap sequencing availablemore broadly. Radical reduction of sequen-cing costs would lead to very differentapproaches to biomedical research.

Genetic variation. Improved genotypingmethods and better mathematical methodsare necessary to make effective use of infor-mation about the structure of variation inthe human genome for identifying thegenetic contributions to human diseases andother complex traits.

The genome parts list. Beyond codingsequences and transcriptional units, newcomputational and experimental approachesare needed to allow the comprehensive deter-

mination of all sequence-encoded functionalelements in genomes.

Proteomics.In the short term,the NHGRIexpects to focus on the development ofappropriate, scalable technologies for thecomprehensive analysis of proteins andprotein machines in human health and inboth rare and complex diseases.

Pathways and networks. As a complementto the development of the genome parts listand increasingly effective approaches to pro-teome analysis,the NHGRI will encourage thedevelopment of new technologies that gener-ate a synthetic view of genetic regulatorynetworks and interacting protein pathways.

Genetic contributions to health, diseaseand drug response. The NHGRI will place ahigh priority on creating and applying newcrosscutting genomics tools, technologiesand strategies needed to identify the geneticbases of medically relevant phenotypes.Research on the genetic contributions to rareand common diseases,and to drug response,will typically involve biological systems anddiseases of primary interest to other NIHinstitutes and other funding organizations.Accordingly, the NHGRI expects that itsinvolvement in this area of research willoften be implemented through partnerships

and collaborations. The NHGRI is particu-larly interested in stimulating researchapproaches to the identification of genevariants that confer disease resistance andother manifestations ofgood health.

Molecular probes, including small mol-

ecules and RNA-m ediated interference, for

exploring basic biology and disease. Explo-ration of the feasibility of expandingchemical genomics in the academic andpublic sectors,particularly with regard to theestablishment of one or more centralizedfacilities, will be pursued by the NHGRI inpartnership with others.

Databases Another type of communityresource for the biological and biomedicalresearch communities is represented by data-bases (Box 3). But their support represents apotentially significant problem. Fundingagencies, reflecting the interest of theresearch community, tend to prefer to usetheir research funds to support the genera-tion of new data, and the ongoing need forcontinued and increasing support for thedata archives and robust access to them isoften given less attention. Both the scientificcommunity and the funding agencies mustrecognize that investment in the creationand maintenance of effective databases isas important a component of researchfunding as data generation. The NHGRI hasbeen a major source of support for severalmajor genetics/genomics-oriented databas-es, including the Mouse Genome Database(www.informatics.jax.org/mgihome/MGD/aboutMGD.shtml), the SaccharomycesGenome Database (genome-www.stanford.edu/Saccharomyces), FlyBase (flybase.bio.indiana.edu), WormBase (www.wormbase.org) and Online Mendelian Inheritance inMan (www.ncbi.nlm.nih.gov/omim). TheNHGRI will continue to be a leader in

exploring effective solutions to the issues ofintegrating, displaying and providing accessto genomic information.

Ethical, legal and social research TheNHGRIs ELSI research activities willincreasingly focus on fundamental, widelyrelevant, societal issues. The community ofscholars and researchers working in thesesocial fields, as well as the scope of issuesbeing explored, need to be expanded. TheELSI research community must includeindividuals from minority and other com-munities that may be disproportionately

affected by the use or misuse ofgenetic infor-mation. New mechanisms for promotingdialogue and collaboration between the ELSIresearchers and genomic and clinicalresearchers need to be developed; suchexamples might include structural rewardsfor interdisciplinary research, intensivesummer courses or mini-fellowships forcross-training,and the creation of centres ofexcellence in ELSI studies to allow sustainedinterdisciplinary collaboration.

Longitudinal population cohort(s) Thispromising research resource will be sobroadly applicable, and will require such

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extensive funding that,although the NHGRImight have a supporting role in design andoversight, success will demand the involve-ment and support of many other fundingsources.

Non-genetic factors in health and disease Aconsequence of an improved definition ofthe genetic factors underlying human health

and disease will be an improvement in therecognition and definition of the environ-mental and other non-genetic contributionsto those traits. This is another area in whichthe NHGRI will be involved through thedevelopment of new strategies and by form-ing partnerships.

Use of genomic information to improvehealth care The NHGRI will catalysecollaboration between the diverse scholarlydisciplines whose joint efforts will be neces-sary for research on the best ways for patientsand healthcare providers to make effectiveuse of personalized genetic information inthe improvement of health. The NHGRIwill also strive to ensure that research inthis area is informed by, and extendsknowledge of, the societal implicationsofgenomics.

Improving the health of all people It will beimportant for the NHGRI to supportresearch that explores how to ensure thatgenomic information is used, to the extentthat such information is relevant, to reduceglobal health disparities. That will include avigorous effort to increase the representationof minorities in the ranks of genomics

researchers.But the full solution of the healthdisparities problem can only come aboutthrough a committed and sustained effort bygovernments, medical systems and society.

Policy development The NHGRI will con-tinue to help facilitate public-policy devel-opment in the area of genetic/genomicscience. Effective policy development willrequire attention to those issues for which itcould have the greatest impact on the policyagenda and could help to facilitate genomicscience.The NHGRI will also focus on issuesthat would assist the public in benefiting

from genomics, such as privacy of geneticinformation, access to genetics services,direct-to-consumer/providers marketing,patenting and licensing of genetic infor-mation, appropriate treatment of humanparticipants in research, and standards,usefulness and quality in genetic testing.

Data releaseAn important lesson of the HGP has beenthe benefit of immediately releasing datafrom large-scale sequencing projects, asembodied in the Bermuda principles(www.gene.ucl.ac.uk/hugo/bermuda.htm).Some other large-scale data production

projects have followed suit (such as thosefor full-length cDNAs and single-nucleotidepolymorphisms), to the benefit of the scien-tific community. Scientific progress andpublic benefit will be maximized by early,open and continuing access to large data setsand by ensuring that excellent scientists areattracted to the task of producing moreresources of this sort. For this system to con-tinue to work, the producers of community-resource data sets have an obligation to makethe results of their efforts rapidly availablefor free and unrestricted use by the scientificcommunity, and resource users have anobligation to recognize and respect the

important contribution made by the scien-tists who contribute their time and efforts toresource production.

Although these principles have been gener-ally realized in the case of genomic DNAsequencing,they have not been for many othertypes of community-resource projects (struc-tural biology coordinates or gene expressiondata,for example). The development of effec-tive systems for achieving the rapid release ofdata without restrictions and for providingcontinued widespread access to materials andresearch tools should be an integral compo-nent of the planning and development of new

community resources.The scientific commu-nity should also develop incentives to supportthe voluntary release ofsuch data before publi-cation by individual investigators, by appro-priately rewarding and protecting the interests

of scientists who wish to share their data withthe community in such a generous manner.

Quantum leapsIt is interesting to speculate about potentialrevolutionary technical developments thatmight enhance research and clinical applica-tions in a fashion that would rewrite entireapproaches to biomedicine. The advent of

the polymerase chain reaction, large-insertcloning systems and methods for low-cost,high-throughput DNA sequencing areexamples of such advances that have alreadyoccurred.

During the course of the NHGRIs plan-ning discussions, other ideas were raisedabout analogous technological leaps thatseem so far off as to be almost fictional butwhich,if they could be achieved,would revo-lutionize biomedical research and clinicalpractice.

The following is not intended to be anexhaustive list, but to provoke creativedreaming:x the ability to determine a genotype at

very low cost, allowing an associationstudy in which 2,000 individualscould be screened with about 400,000genetic markers for $10,000 or less;

x the ability to sequence DNA at coststhat are lower by four to five ordersof magnitude than the current cost,allowing a human genome to besequenced for $1,000 or less;

x the ability to synthesize long DNAmolecules at high accuracy for $0.01per base, allowing the synthesis ofgene-sized pieces of DNA of any

sequence for between $10 and$10,000;

x the ability to determine the methyla-tion status of all the DNA in a singlecell;and

x the ability to monitor the state of allproteins in a single cell in a singleexperiment.

ConclusionsPreparing a vision for the future ofgenomicsresearch has been both daunting and exhila-rating. The willingness of hundreds ofexperts to volunteer their boldest and best

ideas,to step outside their areas ofself-inter-est and to engage in intense debates aboutopportun ities and priorities, has added arichness and audacity to the outcome thatwas not fully anticipated when the planningprocess began. To the extent that this articlecaptures the sense of excitement of the newdiscipline of genomics, it is to their credit.Acomplete list of the participants in this plan-ning process can be found at www.genome.gov/About/Vision/Acknowledgements.

A final word is appropriate about thebreadth of the vision articulated here. Achoice had to be made between portrayinga broad view of the future of genomics

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research and focusing more narrowly on thespecific role ofthe NHGRI.Recognizing thatresearchers and the public are more interest-ed in the promise of the field than about thefunding source responsible,we have focusedhere on the broad landscape of scientificopportunity. We have, however, identifiedthe areas that are particularly appropriate forleadership by the NHGRI throughout this

article. These are generally research areasthat are not specific to a part icular disease ororgan system, but have broader biomedicaland/or social implications.Yet even in thoseinstances, the word partnership appearsnumerous times intentionally. We expect tohave partnerships not only with other publicfunding sources, such as the other 26 NIHinstitutes and centres, but also with manyother governmental agencies, private foun-dations and private-sector organizations.Indeed,publicprivate partnerships,such asthe SNP Consortium, the Mouse SequencingConsortium and the International HapMapProject, provide powerful new models forthe generation of public data sets withimmediate and far-reaching value. Thus,many of the most exciting opportunities ingenomics research cross traditional bound-aries of specific disease definitions, classi-cally defined scientific disciplines, fundingsources and public versus private enterprise.The new era will flourish best in an environ-ment where such traditional boundariesbecome ever more porous.

Although the opportunities describedhere are thought to be highly achievable, theformal initiation of specific programmeswill require more detailed analysis. The rela-

tive priorities of each component must beaddressed in the light of limited resourcesto support research. The NHGRI plans torelease a revised programme announcementand other grant solicitations later this year,providing more specific guidance to extra-mural researchers about plans for the imple-mentation of this vision. Furthermore, ingenomics research, we have learned to expectthe unexpected. From past experience, itwould be surpr ising (and rather disappoint-ing) if biological,medical and social contextsdid not change in unpredictable ways. Thatreality requires that this vision be revisited

on a regular basis.In conclusion, the successful completionthis month of all of the original goals of theHGP emboldens the launch of a new phasefor genomics research, to explore theremarkable landscape of opportunity thatnow opens up before us. Like Shakespeare,we are inclined to say, whats past is pro-logue (The Tempest, Act II, Scene 1). If we,like bold architects,can design and bu ild thisunprecedented and noble structure, restingon the firm bedrock foundation of theHGP (Figure 2), then the true promiseof genomics research for benefitinghumankind can be realized.

Make no litt le plans;they have no magicto stir mens blood and probably willthemselves not be realized. Make big plans;aim high in hope and work, rememberingthat a noble, logical diagram once recordedwill not die, but long after we are gone will bea living thing, asserting itself with ever-growing insistency (attributed to DanielBurnham,architect). sFrancis S. Collins, Eric D. Green, Alan E.

Guttmacher and Mark S. Guyer are at the

National Human Genome Research Institute,

National Institutes ofHealth, Bethesda, Maryland

20892,USA

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Acknowledgements

The formulation of this vision could not have happened without th e

thoughtful and dedicated contributions of a large number of

people. The authors were greatly assisted by Kathy Hudson ,Elke

Jordan,Susan Vasquez,Kris Wetterstrand, Darryl Leja and Robert

Nussbaum.A subcommittee of the National Advisory Council for

Human Genome Research,including Wylie Burke,William Gelbart,

Eric Juengst, Maynard Olson, Robert Tepper and David Valle,

provided a critical sounding board for dr aft versions of this

document. We also thank Aravinda Chakravarti, Ellen Wright

Clayton, Raynard Kington, Eric Lander,Richard Lifton an d Sharon

Terry for serving as working-group chairs at the meeting in

November 2002 that refined th is document. Finally, we thank the

hundreds of individuals who participated as workshop planners

and/or par ticipants during this 18-mont h process.

feature

Documents

Francis S. Collins, Eric D. Green, Alan E. Guttmacher and Mark S. Guyer- A vision for the future of genomics research: A blueprint for the genomic era